Actress Angelina Jolie's disclosure, in 2013, that she had undergone a preventative double mastectomy after testing positive for a mutation in the BRCA1 gene and, in 2015, had a second preventative surgery for the removal of her ovaries and fallopian tubes, helped highlight the fact that inherited gene mutations can put one at increased risk for developing cancer.
Hereditary breast and ovarian cancer syndrome is primarily associated with mutations in the BRCA1 and BRCA2 genes. A woman with an inherited mutation in either gene has a higher chance of developing breast and ovarian cancer in her lifetime than a woman who does not carry such a mutation. Men with the mutation are at higher risk for breast and prostate cancer.

Still, it is estimated that less than one percent of the general population has a mutation in either of these two genes (BRCA is short for BREast CAncer), and that between 10 to 15 percent of women diagnosed with breast cancer have a mutation in either BRCA1 or BRCA2 gene, according to the American Society of Clinical Oncology.

It is further estimated that only 5 to 10 percent of cancer is caused by gene mutations inherited from a parent.

So, who should consider genetic testing to determine their risk for a hereditary cancer?

"There are National Comprehensive Cancer Network guidelines about really what constitutes the higher risk population. Our practice sticks to those guidelines for which patients is genetic testing most appropriate," said Dr. Mary-Alice Abbott, chief of medical genetics, Baystate Medical Center.

"In general, individuals who develop cancer at a younger age, or where there are multiple family members affected, those are the people I would recommend some sort of consultation about thinking about hereditary cancer syndrome in them."

She added, "There are patterns of cancers when we see breast and ovarian cancers in the same family. When we see colorectal cancers in the same family. There are different types of hereditary cancer syndromes that we can assess families for."

Abbott noted that the "risk for carrying a mutation for BRCA1 and 2 can vary somewhat among ethnic groups" and "we know that people of Ashkenazi Jewish background are at particularly high risk."

"We can help sort out who is at highest risk, ask what we can do for people who are worried."

Abbott said when an individual sees a provider in the risk program they generally give a family history in advance.

"They give us information about their family history which we usually evaluate before the visit. We then confirm the information about the family history. Sometimes we ask for records. We might say, 'This is a very concerning history. We need some more information about this person. We need to know what type of cancer, what the age of onset is, maybe what the pathology report looked like,'" Abbott said.

"We determine is this someone who is at relatively high risk for having a genetic cancer condition. It may be there is someone else in the family who is better to first evaluate or it may be that this person is a good candidate for genetic testing."

She said then "we decide what genes are we going to look at."

"Are we going to look at the most common genes or are we going to look at a larger panel of genes and what type of cancer syndrome do we think this is," Abbott said.

"We really try to tailor that testing to the patient and the family history. We talk with the patient quite a bit about what does it mean to have genetic testing. Is this something you are ready to do. Are you ready for the results, positive or negative."

The test itself Abbott said may involve "a blood draw or sometimes there is a saliva collection kit that is used and then that sample is tested for those specific genes and the results are interpreted by the lab and then re-interpreted by the genetic counselor or we have a genetics nurse practitioner, as well as myself, and then we counsel the family about those results."

"What do they mean for this person's health care, is it going to influence their current management and what does it mean for their family members. Does this mean that their children are at risk, does this mean that their brothers and sisters are at risk and then what can we offer them," Abbott said.

She added that "results can be quite conclusive where there is a known variation in the gene that we know is pathogenic. We know it causes disease or disease predisposition."

"However, there can also be changes in the gene. There can be variation in the gene - a variant from the reference sequence that we don't really know what that means. There is not enough data. Modeling programs can't predict how it is going to affect the protein or the body. For those individuals, we have to talk quite a bit about what that means to have what is called a variant of unknown clinical significance," Abbott said.

"These variants are very common. The more genes we test, the more likely we are to find variants. So, for patients in whom we find variants we typically follow them clinically because with time with these variants more and more information is gathered and typically we can eventually say this is a completely normal variation in the gene that we see in other people that doesn't have health implications or indeed this is a disease causing predisposition genetic variant that is a pathological mutation."

She added the fact that with genetic testing "sometimes it is not a yes or no answer" underscores the "value of undertaking it with a genetic counselor."

"They are trained not only in the molecular biology of genetics but also in education and support to really make sure a patient understands what it means to do genetic testing, how to interpret the test results, what the next steps are and really support really through that whole process," Abbott said.

She noted people should be aware of their legal rights in considering genetic testing, as the 2008 Genetic Information Nondiscrimination Act bars employers and health insurers from seeking the results of genetic testing, but this does not apply to life, disability and long-term care insurers.

Abbott added genetic testing is not generally advised for someone who does not have cancer, unless there is a known risk.

"For people who themselves don't have cancer but they may be concerned about something they heard about their family or family members they know about, it is certainly reasonable to have this conversation with your doctor or genetic counselor," Abbott said.

"However, performing genetic testing for someone who themselves isn't affected by cancer is usually not informative. This is because when we test someone who themselves doesn't have cancer and we have a normal test result, it is completely unknown if we have a normal test result because they have not inherited whatever is going on in the family or we did not look for the right thing and there is some other thing in the family that is imposing this increased risk that we never even looked for in this individual."

Abbott added, "When we are evaluating a family, the individual who is most likely to get helpful information for themselves and for their family members is someone who is affected by cancer."

"Oftentimes we will see a patient and we will say, yes we agree we that your family history is concerning. However, for us to really understand this in your family and get some helpful information for you, we need to talk with someone who has been directly affected by the cancer. That is a hard thing to understand," she said.

"Now, if there is a known mutation in a family - for example, you know your sister, your mother or your aunt carries a specific mutation in a specific gene - then it is very easy to determine what your risk is related to that. Testing is straightforward, it is easy to interrupt the results in terms of you being at high or low risk."

Abbott added, "We don't perform genetic testing for conditions that are going to affect us in our adulthood on children."

"We really try to affect the right of the child to make that decision themselves. So, when a child reaches adulthood and is interested in pursuing genetic testing for a known mutation in the family, then we start talking to them about it," Abbott said.

"Their early 20s may not be the right time to perform genetic testing. There may not be any particular interventions for them to do at the time. It may be completely reasonable for them to wait, and so we talk about all of those things on a real individual basis with patients."

Abbott added the completion of the Human Genome Project, in 2003, "allowed us to really start to have the basic map of what are the genes, how many are there and what do they do."

"This very basic information we did not have until that was completed. Now there still remain lots of genes that we have identified, but have no idea what they do. Presumably many of these are involved in human health, but we are slowly chipping away at the contributions of each of these genes," said Abbott of the project that has been described as helping "researchers to begin to understand the blueprint for building a person."

"How this relates specifically to hereditary cancers is that although for quite some years the bigger contributors to hereditary cancers - the genes that really cause a large predispositions that run in families - have been known, we are now finding more genes that either less commonly cause cancer predispositions or that may cause an increased risk to the general population, but not quite as substantially as high risk as some of the earlier identified genes."

Besides genetic testing for hereditary cancer syndrome, Abbott noted that tumors can also be tested "to see how those cells changed from a normal cell to become a cancer cell."

"This is moving from the research arena to some clinical arenas and that can affect how a cancer specialist thinks about treating the cancer," Abbott said.

"More and more therapies are trying to be laser-focused on exactly what is happening at the cellular level. The way these drugs work is complicated. They are expensive and new but really understanding things at this cellular level and being able to target the therapy has very exciting potential. This is really a new area in our ability to personalize treatment."

Still, Abbott said that "the reality of fixing genes that affect every cell in the body is a tremendous challenge."

"Every cell has copy of all the genes sitting there in the cell. But those genes are wound up tight. They get turned on or off when the cell needs them. There are some genes that are very involved in growth. Some genes are very important in fetal life, and in the years during which we are growing. There are cells that are important in regulating cell growth and replication. Those genes are not ones that we want active later in life. There are repair genes that we want to be more active when we age," Abbott said.

"Every gene may not be active in every cell at every time point in our life. Things are shut off, turned on, expressed vigorously, less vigorously and that is something we really think we know more about than we actually do."

She added, "We get the genes that we get when we are born."

"However, the way those genes are expressed and the way those genes function in different cells in different tissues in different parts of our lives are actually heavily influenced by decisions we make about our environment, our exercise, our nutrition and so there is a lot that you can do to keep your genome as healthy as possible," Abbott said.

"I really recommend to everyone maintaining a health lifestyle, avoiding known cancer predisposing things like smoking and get your mammograms. We can only treat what we can detect."

She added that "we know a lot about BRCA1 and BRCA2."

"They were discovered quite a while ago. We understand quite a bit about that - if you have the mutation in those genes, how it affects your lifetime risks for breast and ovarian cancer, but now we are finding additional genes that we knew less about that also can increase risks for cancers, but perhaps not as much of an increased risk as these earlier identified genes," Abbott said.

She added, "Everyone has two copies of BRCA1 and two copies of BRCA2 - they get one from each of their parents, and normally these genes function to healthfully regulate cell growth."

"When people talk about a hereditary cancer syndrome, that means that you have a change in one of your genes that you were born with that exists in all of your cells that may put you at higher risk for cancer. But it is typically other mutations in other genes that is required to actually develop a cancer," Abbott said.

"Having these mutations in your cells puts you at higher risk than the general population, but certainly there are people who may carry the mutation and never develop a cancer."

She added, "Some people who are diagnosed with breast cancer are then found to have one of these hereditary, predispositions to cancer that may affect the way their doctor takes care of their breast or the surgical decisions that are made."

"It may also influence a woman's decisions about other possible treatments that can reduce or eliminate her risk for repeat breast cancer or another cancer, like ovarian cancer," Abbot said.

"Some people chose more frequent screenings, some people chose some medications, some prophylactic medications, like tamoxifen, some people chose surgical prophylaxis like mastectomy or removing their ovaries after their child bearing. So, knowing if you have a hereditary cancer predisposition syndrome may affect the choices that you make with your doctor."

Abbott added, "We often encourage families to share their genetic testing results, a copy of those results with their family members so that it will be straightforward to determine risks and a plan for any of the family members."

"All cancer at the cellular level is genetic in nature. There is some gene problem that happens that leads to cancer. However, there are many fewer of us who are born with a genetic change that puts us at higher risk for developing a cancer. Those can run in families, and those can be passed on from generation to generation," Abbott said.

"Those are the people we are really trying to identify because they are at higher than the general population risk for cancers."